PUBLICATION
Surprising conservation of schizophrenia risk genes in lower organisms reflects their essential function and the evolution of genetic liability
- Authors
- Kasap, M., Rajani, V., Rajani, J., Dwyer, D.S.
- ID
- ZDB-PUB-180719-2
- Date
- 2018
- Source
- Schizophrenia research 202: 120-128 (Journal)
- Registered Authors
- Keywords
- Caenorhabditis elegans, Evolution, Risk genes, Schizophrenia, Synteny, Zebrafish
- MeSH Terms
-
- Animals
- Caenorhabditis elegans/genetics*
- Databases, Genetic
- Drosophila/genetics*
- Genetic Predisposition to Disease/genetics*
- Genome-Wide Association Study
- Risk
- Schizophrenia/genetics*
- Synteny/genetics*
- Zebrafish/genetics*
- PubMed
- 30017463 Full text @ Schizophr. Res.
Citation
Kasap, M., Rajani, V., Rajani, J., Dwyer, D.S. (2018) Surprising conservation of schizophrenia risk genes in lower organisms reflects their essential function and the evolution of genetic liability. Schizophrenia research. 202:120-128.
Abstract
Schizophrenia is a devastating psychiatric illness that affects approximately 1% of the population. Genetic variation in multiple genes causes elevated risk for the disorder, but the molecular basis is inadequately understood and it is not clear how risk genes have evolved and persisted in the genome. To address these issues, we have identified orthologs/homologs of 344 schizophrenia risk genes (from the Psychiatric Genomics Consortium dataset) in lower organisms, including C. elegans, Drosophila and zebrafish, along with phenotypes produced by genetic disruption in C. elegans. Schizophrenia risk genes were evolutionarily conserved at significantly higher rates in C. elegans (81%) and zebrafish (88%) than genes in general for these two species (40-70%). The risk-gene equivalents were highly (~3-fold) enriched for essential genes consistent with polygenic mutation threshold models, which propose that genetic susceptibility results from the inevitable expression of harmful combinations of risk variants in the population. Most notably, numerous examples of cross-species synteny revealed how blocks of risk genes geared toward a shared biological purpose coalesced into proximity during evolution. We obtained initial evidence that schizophrenia risk genes affected different stages of development, potentially allowing differential modulation by the environment. Taken together, studies of the conservation of schizophrenia risk genes in simple model organisms provided novel insights into the molecular basis for genetic susceptibility to a complex human psychiatric disorder.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping